EPO is a hormone that promotes growth of red blood cell consisting of 165 amino acids. EPO is mainly produced in the kidney and partly in the liver, and the production thereof increases under low oxygen conditions.
Anemia refers to a condition showing low levels of red blood cell and hemoglobin in the blood. The symptoms thereof are derived from oxygen deficiency due to decreased number of red blood cells, or changes of the circulation dynamics due to increased breathing rate and cardiac rate to compensate for the oxygen deficiency, and include “general sick feeling”, “easily-fatigued”, “short breath”, “palpitation”, “heaviness of the head”, “dizziness”, “bad complexion”, “shoulder stiffness”, “difficulty in awakening in the morning” and the like.
The cause of anemia is largely divided into low production, promoted destruction and promoted loss of red blood cells, and anemia includes anemia due to hematopoiesis abnormality in the bone marrow, anemia due to shortage of iron, vitamin B12 or folic acid, bleeding during accident or operation, anemia associated with chronic inflammation (autoimmune diseases, malignant tumor, chronically-transmitted diseases, plasma cell dyscrasia etc.), anemia associated with endocrine diseases (hypothyroidism, autoimmune polyglandular syndrome, type IA diabetes, dysfunctional uterine bleeding etc.), anemia associated with chronic cardiac failure, anemia associated with ulcer, anemia associated with hepatic diseases, senile anemia, drug-induced anemia, renal anemia (anemia associated with renal failure), anemia associated with chemical therapy, and the like.
In 1989, a gene recombinant human EPO preparation was approved by the U.S. Food and Drug Administration (FDA) for application to renal anemia, anemia associated with AZT treatment of HIV patients, anemia associated with chemical therapy of cancer patients, or for reduction of blood transfusion volume for patients who underwent an operation. Moreover, its application has been spreading to anemia of prematurity and the like.
Renal anemia is treated with an erythropoiesis stimulating agent (ESA). Renal anemia is mainly caused by decreased EPO production in the interstitial cells in the periphery of renal tubule of the kidney. It is an application wherein gene recombinant human erythropoietin is highly often used for supplement of EPO. Gene recombinant human erythropoietin has strikingly reduced the number of patients in need of periodic blood transfusion, improved various symptoms associated with anemia and greatly contributed to the improvement of ADL (Activities of daily living) and QOL (Quality of Life). On the other hand, being a biological preparation, it is expensive and requires high medical expenses. In addition, it has a short half-life in blood and requires 2-3 times of intravenous administration per week from the dialysis circuit in hemodialysis patients. Thus, the injection frequency is desired to be decreased to prevent medical accidents, and also from the aspects of the amount of medical practice and waste. Furthermore, for peritoneal dialysis patients and patients with renal failure in predialysis period, for whom subcutaneous administration affording a longer period of duration has been employed, once per one or two weeks of administration is still necessary. In this case, the patients often need to go to the hospital only for the administration of gene recombinant human erythropoietin, causing burden on the patients.
Moreover, a long-acting EPO medicament having a prolonged half-life in blood by intravenous injection or subcutaneous injection has been developed by modifying EPO by adding a new sugar chain or PEG chain. However, since only injection preparations have been developed, an orally administrable ESA is desired to prevent medical accidents and reduce burden on patients.
Moreover, an orally administrable ESA is expected to be applicable to a wider range of treatments for not only renal anemia but also anemia caused by various causes.
As a representative molecule promoting transcription of EPO, Hypoxia Inducible Factor (hereinafter to be also referred to as “HIF”) can be mentioned. HIF is a protein consisting of a heterodimer having an oxygen regulatory α-subunit and a constitutionally-expressed β-subunit, where proline in the α-subunit is hydroxylated by prolyl hydroxylase (PHD) in the presence of oxygen and the resulting α-subunit is bound to von Hippel-Lindau (VHL) protein and ubiquitinated. However, since α-subunit is not subject to hydroxylation by PHD under low oxygen conditions, it is not ubiquitinated but bound to an intranuclear hypoxia response element (HRE) to promote transcription of EPO present at the downstream of HIF. Therefore, inhibition of the activity of PHD results in the prevention of ubiquitination of HIF and stabilization thereof. Consequently, the EPO production is increased.
Examples of the diseases expected to be improved by inhibiting PHD to stabilize HIF include ischemic cardiac diseases (angina pectoris, myocardial infarction etc.), ischemic cerebrovascular disorders (cerebral infarction, cerebral embolism, transient cerebral ischemic attack etc.), chronic renal failures (ischemic nephropathy, renal tubule interstitial disorder etc.), diabetic complications (diabetic wound etc.), cognitive impairments (dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease etc.) and the like.